Total Synthesis of Sporolide B

Kanai's Lab Literature Seminar (B4 part) Nov. 10th 2010 Junya Kawai (B4) Total Synthesis of Sporolide B

Isolation: from Salinospora tropica (a marine actinomyceta), and it also produces salinosporamide A, a potent inhibitor of the 20S proteasome.

Structure: determined in 2005 (Fenical et al., Org. Lett., 2005, 7, 2731-2734) 7 rings, 10 stereogenic centers, and 22 out of 24 carbons are either oxygenated or sp2 hybridized. Including highly substituted indane system, a 1,4-dioxane ring, an epoxy cyclohexenone hemiacetal, and 13-membered macrolide moiety. Difference between sporolide A and B is only the location of chlorine atom on the benzenoid structure.

Biological activity: None (but the precursor enediyne compound is considered to have an antitumor activity)

Synthetic study: K. Gademann et al., Synthesis, 2010, 4, 631-642 (Biomimetic method) Total synthesis: K. C. Nicolaou et al., Angew. Chem. Int. Ed. 2009, 48, 3449-3453 (Sporolide B ) K. C. Nicolaou et al., J. Am. Chem. Soc. 2010, 132,11350-11363 (Sporolide B, 9-epi-sporolide B) Synthesis of sporolide A has never been reported.

Contents 1. Biomimetic approach 1-1. Hypothetical biosynthesis of sporolides 1-2. Bergman cycloaromatization 1-3. Nucleophilic addition to p-benzyne 1-4. Gademann's synthetic study 2. Nicolaou's approach 2-1. Retrosynthetic analysis 2-2. Hetero [4+2] cycloaddition 2-3. Regioselective [2+2+2] cycloaddition 2-4. Model studies about cycloaddition 2-5. Total synthesis of sporolide B

salinosporamide A

Angew. Chem. Int. Ed., 2010, 49, 2 Chem. Soc. Rev., 2009, 38, 2993 1 1. Biomimetic approach Moore et al., PNAS, 2007, 104, 10376-10381 Moore et al., J. Am. Chem. Soc., 2008, 130, 2406-2407 1-1. Hypothetical biosynthesis of sporolides

OH X OH OH O Y O Me O O OH O MeO O OH 1a: sporolide A (X=H, Y=Cl) 1b: sporolide B (X=Cl, Y=H)

Bergman cycloaromatization

OH OH OH O Me O O OH O O MeO O OH pre-sporolide

pre-sporolide derived from 2 building blocks. 1-2. Bergman cycloaromatization

O R. G. Bergman, Acc. Chem. Res., 1973, 6, 25-31 OH Basak et al., Chem. Rev., 2003, 103, 4077-4094 MeO Enz S O O O OH R3 OH O O R1 R1 R3 OH heat 2 3 R2 9-membered enediyne cyclohexenone epoxide R2 R4 R4 enediyne biradical intermediate (Z)-hex-3-ene-1,5-diyne "para-benzyne"

OH O O O 1,4-cyclohexadiene SCoA HO SCoA (hydrogen donor) CCl4

Acetyl-CoA Malonyl-CoA H2N CO2H H Cl L-Tyrosine R1 R3 R1 R3

Biosynthesis toward pre-sporolide is catalyzed by several R2 R4 R R polyketide synthases encoded in spo gene cluster. 2 4 H Cl 2 Nicolaou et al., J. Am. Chem. Soc., 1988, 110, 4866 Niestroj et al., Eur. J. Org. Chem., 1999, 1-13 Sander et al., Angew. Chem. Int. Ed., 2003, 42, 502-528

Distance between two terminal alkyne moiety is one of the key factors of reactivity. o Cyclization of 27 requires 200 C (t1/2 = 30 s), while 10- membered enediyne 62 proceeds smoothly even at 37oC.

Fenical et al., Org. Lett., 2006, 8, 1024

9-membered enediynes are much more unstable. In nature, they are stabilized as chlomoprotein. Once separated from their protein complex, cyclization occurs rapidly.

Buchwald et al., Science, 1995, 269, 814 Smith and Nicolaou, J. Med. Chem., 1996, 39, 2103-2117

Hydrogen atom abstraction from DNA leads to double-strand cleavage. So, many compounds possesing the enediyne structure has an antitumor activity. For cyclization of the acyclic enediyne, milder temperature can be adopted by bridging two alkyne moiety with transition metals. 3 1-3. Nucleophilic addition to p-benzyne

O'Connor et al., J. Am. Chem. Soc., 2007, 129, 4795-4799

OH H OH Cl OH OH OH OH Slopes are clearly the same for all. O O Cl H Me O Me O O O OH O O OH O O MeO MeO Plausible mechanism O OH O OH sporolide A sporolide B

Cyanosporaside A/B (products of S. pacifica), sprolide A/B were isolated as a 1:1 mixture of Cl-positional isomers. (No dihydro nor dichloro compound was detected.) Not radicalic pathway. The intermediate is haloaryl anion 7 (strong base) + How is only one Cl incorporated ? which can abstract D cation from DMSO-d6. The rate-limiting step is the cycloaromatization of 5 to 6. H/D LiX, pivalic acid Alternative mechanisms of cyclization can be excluded due to the reaction rate order. o DMSO-d6, 37 C Electron transfer from halide to p-benzyne can be rejected, because it is endothermic (>170 kJ/mol). 5 X 8 If the protonation occured before the chlorination, deuterium abstraction from DMSO-d6 would be unreasonable.

A mix of transfers of an electron pair and a single electron.(10)

Singlet biradical forms a new weak sigma bond between position 1 and 4, and halide approachs to the sigma antibond, then nucleophilic displacement occurs. (11, 12)

Calculated study shows this halide addition step is exothermic, even in water.

8 is partially deuterated, even in absent of D2O. Thus, only one chlorine is introduced to either of the Reaction rate is just first order in [5](i.e. -d[5]/ dt = k[5]) two possible positions. and independent of [HA], [LiX], and the kind of halides. 4 1-4. Gademann's synthetic study

Retrosynthetic analysis Biomimetic approach through Bergman cycloaromatization of 9-membered enediyne ring. If this route succeeded, a 1:1 mixture of both isomers could be obtained at the same time.

The most challenging point is the high rigidity of 9-membered enediyne moiety.

OH Me O O OH esterification OH X OH MeO O O X OPG OH O 30 OH Y Me H O OPG O O OH PGO O MeO HO O macrocyclization Y OH HO H OPG 1a: sporolide A (X=H, Y=Cl) 31 1b: sporolide B (X=Cl, Y=H)

Bergman cycloaromatization

OPG OPG H O Acetylide H HO OH O O attack H OPG O O 32 33 Sonogashira cross-coupling 9-membered enediyne intermediate

TBS OTBS O H O O TfO O H O 2-cyclopenten-1-one 34 35

5 Strategy 1) 9-membered enediyne ring K. Gademann et al., Synthesis, 2010, 4, 631-642

OH O O 12 steps CeCl3, LiCl, H O H O O LiN(SiMe2Ph)2 H O O -78 ~ 0oC O O O 2-cyclopenten-1-one 33 No TM Hirama et al., Chem. Lett., 1998, 27, 959

H OH OH CeCl3/LiN(TMS)2 (15eq.), Bergman THF (1mM); SM cycloaromatization O H 25oC, 3h up to 35% yield

Lower temperature (<20oC), or higher concentration (5mM) only yielded dimer or oligomer. A large excess of CeCl3/LiN(TMS)2 was necessary to obtain TM in >10% yield.

Thus, high temp. is required for intramolecular acetylide attack to enediyne, because of the rigidity of structure which came from two sp2 hybridized centers. But in this case, higher temp. made serious side reactions.

Strategy 2) 9-membered diyne ring

OPG OPG HO OH H Target structure; 2 HO OPG 9-membered ring diyne core without two sp hybridized centers (Less rigid structure than enediyne) 36 H O H OH H O H O H DMP 9 steps O 87% O 39 O O H 37 H O

Target structure was not formed in various conditions. O 38

A. Yamashita et al., J. Am. Chem. Soc., 1975, 97, 891 Allenes are known to undergo isomerization to alkynes under strong base condition. So, they continued the synthesis using allene 39.

6 H H O H H H O O H H O O 40 O O : R = H 39 O R O 41: R = TMS 42: R = Me

Strong base Lewis acid Temperature

OH O H O H H O O O O O O O R O R O

Cascade system toward formation of 9-membered ring failed under 22 conditions.

H H H OTBS H OTBS KAPA H O O O O O O Simple isomerization also failed. O O R O O R 43: R = H 44: R = Me 45: R = TBS

KAPA: Potassium 3-(aminopropyl)amide; prepared from KH & 3-aminopropylamine in situ. Yamishita et al., Chem. Commun., 1976, 959

Conclusion 9-membered enediyne ring is very difficult to construct due to the high rigidity of the structure. It is still uncertain whether the strategy of forming 9-membered diyne ring is promising or not.

7 2. Nicolaou's approach K. C. Nicolaou et al., Angew. Chem. Int. Ed., 2009, 48, 3449-3453 K. C. Nicolaou et al., J. Am. Chem. Soc., 2010, 132, 11350-11363

2-1. Retrosynthetic analysis

Instead of biomimetic way, they proposed the approach through two unusual cycloadditions; Intramolecular hetero [4+2] cycloaddition, and ruthenium-catalyzed [2+2+2] cycloaddition. esterification OH Cl esterification (failed) OH (failed) O Cl OAc OH O O O Me OBn O O OH O Me O O MeO OBn OMe OAc O OH hetero [4+2] cycloaddition HO [2+2+2] cycloaddition 1b: sporolide B 2

AcO acetylide O addition esterification OAc O OBn O

Me O Cl

OBn OMe OH OTBS 4 3

O O O O OBn

Me OH HO Li OH OBn OMe Cl 19 20 TMS OTBS 11

8 2-2. Hetero [4+2] cycloaddition

(a) hetero 2e component (b) hetero 4e component X X X [4+2] X [4+2] Y Y Y Y X = O, Y = CR2 (carbonyl) X = O, Y = CR2 (enone) X = Y = NR X = Y = O (1,2-dicarbonyl) Nicolaou's Method

[4+2] cycloaddition of 1,2-dicarbonyl moiety

R1 O R1 R2 O R2 R R

O R3 R4 O R4 R3 o-quinone (o-benzoquinone) 1,4-dioxane derivative

Cycloaddition of substituted ortho-quinones has only been reported. (Simple o-quinones are so unstable that they are rapidly dimerized.)

Difficulties: (1) Two stable C=O bonds C-C : 340-350 kJ/mol (2) Lower HOMO energy than C=C bond C-O : 350-380 kJ/mol (3) Existence of other 2e/4e systems C=C: 600-625 kJ/mol C=O: 725-760 kJ/mol In order to overcome: (1) Aromatization of o-quinones aromatization : 140 kJ/mol (2) Introduction of EDG / Using LUMO of o-quinone (Ref. Warren) (3) Steric effect

V. Nair et al., Synlett., 1996, 1143-1147 o-quinone has 4 possible reactive points.

Reglier et al., Tet. Lett., 2004, 45, 8011-8013

t-Bu O t-Bu O O HO OH O toluene - t-Bu O Ph O reflux, 10h t-Bu O O Ph flavonol 55% (racemic)

Regioselectivity seems to be based on the partial polarization.

9 P. G. Jones et al., Eur. J. Org. Chem., 2006, 335-350

all-carbon diene as 4e system o-quinone derivative heterodiene moiety as 4e system

toluene reflux

62% yield

Reactivity of each diene-system seems to depend on the structural bulkiness of dienophile.

reacts with all-carbon diene reacts with both (gives mixture)

reacts with heterodiene moiety

10 K. Itoh et al., Chem. Commun., 2000, 549-550 2-3. Regioselective [2+2+2] cycloaddition K. Itoh et al., J. Am. Chem. Soc., 2003, 125, 12143-12160 Y. Yamamoto et al., Chem. Rev., 2000, 100, 2901-2915 General mechanism

M = Co, Ni, Rh, Ru, Pd and many other kinds of metals are available today.

Generally, highly regioselective synthesis is achieved in partially / totally intramolecular system.

Holmquist et al., J. Am. Chem. Soc., 1995, 117, 6605-6606

Catalyst screening in entry 1 (above) 10 mol% 6a

(10 eq.)

Cp*RuCl(cod) gives the greatest meta-selectivity.

The bulky Cp* ligand is important for the high selectivity. (Cp* = pentamethylcyclopentadienyl) Willkinson's catalyst was used. Steric repulsion causes regioselectivity. meta-substituted benzene can be synthesized For regioselective synthesis of pyridine derivatives, through this approach. see Mr. Saito's literature seminar. 11 2-4. Model studies about cycloaddition

In the first retrosynthetic analysis, they proposed 2 pathways.

Path a: Intermolecular [4+2] and following lactonization Path b: Esterification and following intramolecular [4+2]

But intramolecular [4+2] cycloaddition might be problematic, due to the limited conformation.

So they adopted the intermolecular [4+2] system (Path a) as an initial study.

Intermolecular [4+2] cycloaddition ~ model study

o- quinone has two kinds of diene system: all-carbon diene, and hetero diene moiety. OBn OMe All-carbon diene has much higher reactivity for [4+2], but is more sterically hindered. Me OEt Indene 16 gives only undesired products. (all-carbon diene is much more reactive.) O But more crowded indene derivative 18 gives desired products in good yield. O Steric repulsion of dienophile can reverse the reactivity of diene system ! all-carbon O diene In case of enone 20, all-carbon diene reacts, despite the steric repulsion. hetero diene 6 In all cases, regioselectivity can be explained by assuming polarization. (diene: electron donation from OBn group. dienophile: conjugation with phenyl or carbonyl group.) 12 Failed attempts through macrolactonization HO

OBn OMe Me OEt toluene OEt 115oC, 3h Me BnO O O O O OH 62% O O 6 7 MeO 6,7-TS

OH HO HO 3 steps OEt HO Me Macrocycle Me BnO BnO O O O O MeO O MeO O

Macrolactnization failed in 6 activation conditions (Corey-Nicolaou, Mukaiyama salt, Mitsunobu, etc.) Due to overwhelming strain within the expected transition state for the macrolactonization...?

Change the method to Path b (esterification & following intramolecular [4+2] cycloaddition)

Intramolecular [4+2] cycloaddition ~ model study

Ag2O Bn

120oC

38 1 step, 60% yield

H2 Pd(OH)2 85%

1) PMBOH PIFA tBuOOH 87% DBU H 2) DDQ 96% 60% H 40 39 Sporolide model system

In model study, desired macrocycle was formed as a single diastereoisomer.

13 Diastereoselectivity of model study Strategy change from esterification to [2+2+2] cycloaddition

difficult to construct

Diastereo- & regioselectivity is fully controled by partial polarization and 1,3-allylic strain.

To synthesize precursor VII through esterification, VIII and IX is necessary. Though synthesis of VIII was achieved, IX was difficult to construct, presumably due to sensitive & crowded nature.

As an alternative strategy to synthesize precursor VII, metal-catalyzed [2+2+2] cycloaddition was adopted.

14 Possible selectivity of [2+2+2] cycloaddition

OH X OH O X OAc OH O O Y Me hetero [4+2] O OBn O O OH O Me O O MeO OBn OMe OAc Y O OH HO

1a: sporolide A (X = H, Y = Cl) sporolide A: ortho position (unfavor) 2a: sporolide B (X = Cl, Y = H) sporolide B: meta position (favor)

Considering the regioselectivity of [2+2+2] cycloaddition, the substituted group (o-quinone moiety) and chlorine atom will locate in meta position. Only sporolide B can be synthesized through [2+2+2] cycloaddition !

Failed attempt to sporolide B system through intramolecular [4+2] cycloaddition

62 77% yield

OH Cl OH HO O 9 Me O 9 O O OH O MeO O OH

1b: sporolide B

In case of fully substituted precursor 62, [4+2] cycloaddition didn't occur at all, due to the steric clash between o-quinone moiety and down-directed OBn group at C-9 position.

To overcome this problem, new substrate with the C-9 inverted stereochemistry was essencial. 15 2-5. Total synthesis of sporolide B

Synthesis of building block 3

Curran et al., Tetrahedron, 1997, 53, 1983 Braun et al., J. Am. Chem. Soc., 1993, 115, 11014 O SP-435 (Lipase) I 2 steps isopropenyl acetate HO OH AcO OH OH O 50%, 98% ee 4 steps OTBS furfuryl alcohol cis-1,4-cyclopentenediol 5 4,200 YEN/ 50G (Ald) 68,500 YEN/ 2.5g (Ald)

O . OBn O OBn I 1) NaBH4, CeCl3 7H2O I PdCl2(PPh3)2 (5 mol%) MeOH, -78oC, 1h CO (balloon), Et3N MeO

2) NaH, THF; BnBr, TBAI MeOH, 70oC, 3h (95%) OTBS 0oC to rt, 16h OTBS OTBS (95%, ca. 10:1 dr) 5 6 7 >99% ee 1) DIBAL (2.5eq.), toluene -78oC to -10oC, 1h (95%) . o 2) DHP, TsOH H2O, CH2Cl2, 0 C, 30min. 3) TBAF, THF, rt, 3h

OTHP OBn 1) NaBH , CeCl .7H O OTHP OTHP OBn 4 3 2 OBn 1) DMP, NaHCO3, CH2Cl2, rt, MeOH, -78oC, 1h 30min. (83% over 3 steps)

2) TBSCl, imid., DMAP 2) I , CH Cl /Pyridine (1:1) I 2 2 2 CH Cl , rt, 3h I rt, 15h (80%) OTBS 2 2 (94%, ca. 10:1 dr) O OH 10 9 8

1)TMS PdCl2(PPh3)2 (2 mol%), CuI (4 mol%), Et2NH, rt, 16h (98%) o 2) Et2AlCl, CH2Cl2, -25 C to rt, 2h (99%) 3) DMP, NaHCO3, CH2Cl2, rt, 1h (79%)

Cl Cl OH O O OBn OBn OBn (4.5 eq.) MeLi (3.0 eq.), Et2O o DMP, NaHCO3 0 C, 30min.; Cl Cl CH Cl , rt, 1h o 2 2 OTBS then 11, 0 C, 10min. TMS OTBS 93% (2 steps) TMS OTBS TMS 11 (ca. 5:1 dr) 12 13 undesired diastereomer DIBAL (1.5 eq.), toluene -78oC, 30min. (ca. 7:1 dr)

OAc OBn 1) K2CO3, MeOH OH OBn rt, 1h (99%) (TMS deprotection) Cl Cl 2) Ac2O, Et3N, DMAP OTBS o CH2Cl2, 0 C, 30min. TMS OTBS (98%) 3 14 (81% pure isomer) 16 stereoselectivity of propargylic alcohol 12 and 14

12 14: direct Mitsunobu rxn failed. oxidation-reduction was adopted.

Chelation-controled TS carbonyl group is directed to up-side.

13 11-TS

Lithium chloroacetylide is formed in situ. MeLi Cl Cl MeLi H Cl Li Cl H H CH4 LiCl, CH4

The configurations of 12/14 were determined by NMR (NOE?) of derivatives, prepared by [2+2+2] cycloaddition.

OH OBn OTBS HO OBn

Cl OPMB Cl (S) Ru-catalyzed PMBO TMS OTBS [2+2+2] cycloaddition OTBS TMS 12 or 14 TBSO

Synthesis of building block 4

A. Kubo et al., J. Chem. Soc. Perkin Trans. 1, 1997, 53-69

O O O O O n mCPBA; O MOMCl O BuLi, THF; O

KOH-H2O, DMF MeI MeOH Me O H OH OMOM OMOM

Piperonal Sesamol HCl 5,100 YEN /100G 13,200 YEN /25G N EtOH

N N O O N O O O BnX (hexamethylenetetraamine) O

H H AcOH Me Me Me OBn O OH O OH 15

17 Synthesis of building block 4

O O O O O AD-mix- O tBuOH/H O (1:1) Ph3P CH2 2 H H Me o Me OH Me THF, 0oC, 30min. 25 C, 8h OBn O (98%) OBn (96%, 98% ee) OBn OH 15 16 17

o 1) TBSCl, Et3N, DMAP, CH2Cl2, 25 C, 8h (99%) 2) tBuOK, MeI, MeCN, 0 to 25oC, 16h (95%) 3) TBAF, THF, 25oC, 16h (99%) O O O 1) DMP, NaHCO , CH Cl , 25oC, 1h (78%) O 3 2 2 O . 2) NaClO2, NaH2PO4 2H2O, 2-methyl-2-butene Me OH t o BuOH/H2O (1:1), 25 C, 30min. (96%) Me OH OBn OMe Pinnick oxidation OBn OMe 19 18

20, EDCI, DMAP HO CH Cl , 25oC, 3h (73%) 2 2 OH 20 AcO O O O O O Pb(OAc)4 O

Me O benzene, 75oC, 1h Me O OBn OMe OH (89%) OBn OMe OH

21 4

Preparation of 20

Yadav et al.,Tet. Lett.,1988, 29, 2737

OH O HO OH HO OPMB HO NaH (1 eq.) OH 2 steps OO PMBBr (1 eq.) OO O OH

D-(-)-tartaric acid PPh3 CCl4, reflux

Cl OPMB OH DDQ (2 eq.) LiNH (6 eq.) OPMB 2 OH OO CH2Cl2/H2O OH liquid NH3 20

18 18 19 : Dess-Martin oxidation & Pinnick Oxidation

Dess-Martin oxidation: A milder oxidation method of alcohol aldehyde (cf. Swern oxid.) Pinnick oxidation: A milder oxidation method of aldehyde carboxylic acid Aldehyde-selective oxidation (alcohol, alkene etc. are not oxidized.) AcO OAc (2-methyl-2-butene is the hypochlorous acid scavenger.) I OAc If Mn(VII) or Cr(VI) is used (1 step oxidation), benzylic oxidation may also occur. O

H H O O DMP oxid. O O Pinnick oxid. O Cl Dess-Martin R OH Cl Periodinane O R H O R H 18

H O O O O Cl H Cl R R OH H hypochlorous acid O 19

19 21 : Milder condensation

EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Cl Me Me HCl Me N N NC N Me Me Me N N H

21 4: Radicallic cleavage? Chepelev et al., J. Org. Chem., 2003, 68, 7023-7032

Me Me O O H AcO (AcO) Pb O (AcO)2Pb O 3 O - AcOH O O - Pb(OAc)2 O O O

Me R Me R Me R OBn OBn OBn 21 4

19 Synthesis of o-quinone derivative 2 (through Ru-catalyzed [2+2+2] cycloaddition)

OAc OBn OAc Cl OBn

Cl *Cp Ru Ru Cl OTBS Cl TBSO 3 (1.1 equiv.) (7 mol%) AcO o 3-TSa O DCE, 25 C, 30min. O Oxidative addition O Free-hydroxy group directing alkyne coordination Me O OBn OMe OH OAc AcO *Cp Cl 4 (1.0 equiv) Cl OBn O O Ru O

Me O TBSO OH OBn OMe 3-TSb

Alkyne insertion to metallacycle

AcO O Cl OAc AcO O O Cl Cl O *Cp OBn O Ru OAc O Me O OBn OMe OH Reductive Me O OBn TBSO elimination OBn OMe OH 22 (87% yield) TBSO

o 3-TSc 1) Ac2O, Et3N, DMAP, CH2Cl2, 0 C, 30min. (92%) 2) aq. HF (excess), MeCN, 25oC 30min.; then MeOH(excess), 25oC, 3h (74%) deprotection of TBS & acetoxy acetal group

OH Cl OAc O Cl OAc HO O O OBn O Ag2O (2.5 eq.) OBn

Me O o Me O CH2Cl2, 25 C, OBn OMe OAc 30min. (94%) OBn OMe OAc HO HO

23 2

20 Several Studies about [2+2+2] cycloaddition step

4 22

87% yield

4 22'

Regioselectivity is completely controled by steric effect ! (No ortho-regioisomer was observed at all)

Free hydroxy group of 4 fastens the reaction, because of the possible coordination onto ruthenium nucleus. When propargylic alcohol 4 was acetylated in advance, reaction rate got significantly slower (ca. 10-fold) and regioselectivity decreased (ca. 10:1).

Wilkinson's catalyst Rh(PPh3)3Cl can also catalyze this cycloaddition (meta:ortho 20:1, 85% combined yield). For this time, erosion of regioselectivity was also observed (20:1 10:1), when acetyl-protected 4 was used.

Sporolide A cannot be synthesized through the same method !

OH O OAc OH O OH O OBn O Cl Me O Me O O O OH O OBn OMe OH Cl HO MeO 1a: sporolide A O OH ortho-substituted component is required. OAc OBn OBn OMe OH OAc AcO Me O OBn O O O OTBS Cp*RuCl(cod) O O Cl O Cl Me O HO Undesired meta- OBn OMe OH substituted compound.

21 Synthesis of Sporolide B from 2 (through hetero [4+2] cycloaddition)

OAc O Cl Cl OAc OAc O O OBn OBn O 9 9 Me OH Me O o BnO toluene, 110 C, 1.5h O OBn OMe OAc O HO MeO O 2 2-TS

Intramolecular hetero [4+2] cycloaddition

OAc Cl OAc OAc Cl OAc O OH 1) TESOTf, Et N, CH Cl 9 3 2 2 OBn Me OTES 0oC, 30min. (90%) O 9 HO Me O BnO OH O O 2) H2, Pd(OH)2/C O MeO O EtOAc, 25oC, 4h (92%) MeO O 25 24 Ph O O (40% yield based on PIFA (1.5 eq.), PMBOH, K2CO3 ca. 50% conversion) MeCN, 0oC, 30min. (75%) I F3C O O CF3 Oxidative dearomatization PIFA

OAc Cl OAc Cl OAc OAc OH O O 9 OTES O 9 OH Me Me O O O O 1) DMP, CH2Cl2, O o O O 25 C, 1h (90%) O Me4NBH(OAc)3 (10 eq.) MeO MeO OAc OPMB OPMB Cl 2) aq. HF (excess) MeCN/AcOH (10:1) o OAc 26 MeCN, 25oC, 2h 27 25 C, 2h (85%) OH (85%) O 9 Me O O O OH O MeO OPMB OH Cl OH OH Cl 28 OH OH O OH Me O O Me O OH O O tBuOOH (10 eq.) O OH O O O MeO O OH DBU, CH2Cl2, MeO 1) DDQ (5 eq.), CH2Cl2/H2O (10:1) OH o 40oC, 3h (63%) 25 C, 5h (70%) 1b: sporolide B 2) DBU, CH2Cl2/MeOH (3:1) 29 40oC, 4h (78%) 22 25 26: Oxidative dearomatization by PIFA (formation of p-benzoquinone monoacetal)

Y. Kita et al., J. Org. Chem., 1987, 52, 3927-3930

Ph O I O OH PIFA (1 eq.) O O CF3 K2CO3 (2 eq.)

MeOH, MeCN O o O 0 C to rt, 10min. O MeO O O O 83% yield MeOH

Conclusion

Hetero [4+2] cycloaddition of o-quinone is sometimes useful for construction of benzodioxin moiety, but there seems to be much room to improve in this reaction.

Partially-intramolecular [2+2+2] cycloaddition of alkynes has now become one of the most powerful way to synthesize highly substituted benzene derivatives under mild conditions.

In both cycloadditions, chemo- & regioselectivity highly depends on the steric effect of the substrates and the catalyst.